RIPK2/MKK7/c-Myc Signaling as a Therapeutic Target in Prostate Cancer Metastasis

RIPK 2/MKK 7/c-Myc信号通路作为前列腺癌转移的治疗靶点 摘要：尽管前列腺癌（PC）治疗取得了进展，但远处转移仍然是一个主要原因 PC的发病率和死亡率，造成重大的社会和经济负担。三个最近的III期临床 试验（即，SPARTAN、PROSPER和ARAMIS）明确表明，预防或延迟PC 转移提供了强有力的临床益处，将中位总生存期延长了10-14个月。保持 增强势头，进一步提高PC的无转移生存期（总生存期的强有力替代品） 在PC转移患者中，迫切需要鉴定新的可药物靶点并描述其治疗效果。 行动机制（MoAs）。通过对三个临床组学数据库的综合分析， 受体相互作用蛋白激酶2（RIPK 2）作为PC转移的首选药物靶点候选者。RIPK 2是 在65%的致死性转移性去势抵抗性PC中扩增/获得，其mRNA过表达与 疾病进展和预后不良。RIPK 2敲除（RIPK 2-KO）或用强效RIPK 2治疗 抑制剂（例如，FDA批准的泊那替尼）显著抑制PC细胞侵袭和集落形成， 在体外不增殖，在体内将22 Rv 1细胞的转移降低高达92%。机械地，独特的 从经典的NOD/RIPK 2/NF-κB途径，RIPK 2强烈调节c-Myc的稳定性和活性（a PC转移的驱动程序），主要是通过结合和激活MKK 7，我们将其鉴定为一种新的直接c-Myc- S62激酶。这种非经典的RIPK 2/MKK 7/c-Myc信号通路可以被RIPK 2-KO有效地灭活 或泊那替尼，因此是PC转移中非常有希望的药物靶标。在这里，我们的总体目标是提供 通过检验中心假设：RIPK 2/MKK 7/c-Myc信号传导是一个强有力的临床试验科学依据。 与PC进展、转移和患者预后不良相关，对RIPK 2依赖性 PC转移，其抑制是泊那替尼抑制PC的主要（尽管不是唯一）MoA 转移PI组建了一支优秀的多学科团队，以实现三个不同但相互关联的目标。 具体目的：1）评估RIPK 2/MKK 7/c-Myc信号传导的临床相关性并完善其分子基础， 2)确定RIPK 2-KO是否主要通过灭活MKK 7/c-Myc信号传导来抑制PC转移 3）确定泊那替尼是否主要通过灭活RIPK 2/MKK 7/c- Myc信号传导，并定义泊那替尼在抑制PC转移中的RIPK 2非依赖性MoA。如果成功， 这些研究将揭示PC转移的一个新的致命弱点，并揭示RIPK 2的主要MoAs- KO和泊那替尼抑制PC转移。他们将提供有价值的临床前数据，以指导 开发一项临床试验，重新利用泊那替尼，以大幅改善患者的临床结局， 转移性PC的风险。鉴于RIPK 2和MYC共扩增/获得在多种癌症中的高患病率， 类型，拟议研究发现的MoA将具有超出PC空间的临床意义。

RIPK2/MKK7/c-Myc Signaling as a Therapeutic Target in Prostate Cancer Metastasis ABSTRACT: Despite progress in prostate cancer (PC) therapeutics, distant metastasis remains a major cause of morbidity and mortality of PC, imposing significant social and economic burdens. Three recent phase III clinical trials (i.e., SPARTAN, PROSPER, and ARAMIS) unequivocally demonstrated that preventing or delaying PC metastasis provides strong clinical benefits, prolonging the median overall survival by 10-14 months. To keep up the momentum and further improve the metastasis-free survival (a strong surrogate of overall survival) of PC patients, there is an urgent unmet need to identify novel druggable targets in PC metastasis and delineate their mechanisms of action (MoAs). Through an integrated analysis of three clinical omics databases, we identified receptor-interacting protein kinase 2 (RIPK2) as a top druggable target candidate for PC metastasis. RIPK2 is amplified/gained in 65% of lethal metastatic castration-resistant PC and its mRNA overexpression is associated with disease progression and poor prognosis. RIPK2 knockout (RIPK2-KO) or treatment with a potent RIPK2 inhibitor (e.g., the FDA-approved ponatinib) significantly suppressed PC cell invasion and colony formation but not proliferation in vitro and reduced the metastasis of 22Rv1 cells by up to 92% in vivo. Mechanistically, distinct from the canonical NOD/RIPK2/NF-κB pathway, RIPK2 strongly regulates the stability and activity of c-Myc (a driver of PC metastasis), largely by binding and activating MKK7, which we identified as a novel direct c-Myc- S62 kinase. This noncanonical RIPK2/MKK7/c-Myc signaling pathway can be potently inactivated by RIPK2-KO or ponatinib and thus is a very promising drug target in PC metastasis. Here, our overall goal is to provide a strong scientific rationale for a clinical trial by testing a central hypothesis: RIPK2/MKK7/c-Myc signaling is associated with PC progression, metastasis, and poor prognosis in patients and is critical for RIPK2-dependent PC metastasis, and its inhibition is the primary (albeit not the only) MoA of ponatinib in suppressing PC metastasis. The PI has assembled an outstanding multi-disciplinary team to pursue three distinct but interrelated specific aims: 1) assess the clinical correlations and refine the molecular basis of RIPK2/MKK7/c-Myc signaling, 2) determine whether RIPK2-KO inhibits PC metastasis primarily by inactivating the MKK7/c-Myc signaling pathway, and 3) determine whether ponatinib impairs PC metastasis primarily by inactivating RIPK2/MKK7/c- Myc signaling and define RIPK2-independent MoAs of ponatinib in suppressing PC metastasis. If successful, the proposed studies will expose a novel Achilles’ heel for PC metastasis and reveal the major MoAs of RIPK2- KO and ponatinib in suppressing PC metastasis. They will provide valuable preclinical data to guide the development of a clinical trial repurposing ponatinib to substantially improve the clinical outcomes of patients at risk for metastatic PC. Given the high prevalence of RIPK2 and MYC co-amplification/gain in multiple cancer types, the MoAs uncovered by the proposed studies will have clinical implications beyond the PC space.